SPHINGOLIPID MEDIATORS AND INTESTINAL TUMORIGENESIS

项目总结(见说明)： 食物中的鞘磷脂在肠道中被强烈地代谢成极性代谢物，如鞘氨醇和1-磷酸鞘氨醇(S1P)。美林及其同事 研究表明，在致癌物诱导和肿瘤抑制基因缺失(ApcMin/)的肠道肿瘤发生模型中，饮食中的鞘磷脂具有化学预防作用。此外，增加鞘磷脂-RLCH饮食(如大豆)的摄入量，提高细胞内鞘氨醇水平，与降低肠癌的发病率有关。这些数据表明鞘脂介体是肠道肿瘤发生的强有力的调节剂。 这一建议是基于这样的假设，即鞘氨醇激酶是一种关键的调节酶，通过抑制肿瘤抑制物脂鞘氨醇的细胞内水平和增强促肿瘤形成的脂质介质SIP来促进肠道肿瘤的发生。我们建议进一步确定分子机制，并在小鼠肠癌模型中测试其生物学意义。因此，具体目标是： 1.进一步明确鞘氨酸激酶在肠道肿瘤发生中的作用。 2.明确鞘氨醇细胞内信号转导的分子机制， 3.我们将验证Sphk酶基因缺失带来的细胞内鞘氨醇增加和81P自分泌信号减少与肿瘤抑制作用有关的假说。饮食中的鞘磷脂将被用来进一步提高Sphk基因敲除小鼠的鞘氨醇水平，我们将测试这种饮食操作是否会进一步影响ApcMin/-t-模型中的肠道肿瘤发生。 由于肠道中的鞘脂水平可以通过饮食方式改变，这项研究有望提供一种新的癌症化学预防方法。

PROJECT SUMMARY (See instructions): Sphingolipid mediators, are involved in complex cell signaling pathways that regulate cell growth, apoptosis and differentiation. Dietary sphingomyelin is avidly metabolized in the intestinal tract into polar metabolites such as sphingosine and sphingosine 1-phosphate (S1P). Our laboratory defined the first G protein-coupled receptor for SIP and characterized its receptor-dependent actions. Merrill and colleagues have shown that dietary sphingomyelin is chemopreventive in carcinogen-induced and tumor-suppressor gene deleted (ApcMin/+) models of intestinal tumorigenesis. In addition, increased intake of sphingolipid-rlch diets (such as soy), which raises intracellular sphingosine levels is associated with reduced Incidence of intestinal cancer. These data suggest that sphingolipid mediators are potent modulators of intestinal tumorigenesis. This proposal is based on the hypothesis that sphingosine kinase is a key regulatory enzyme that facilitates intestinal tumorigenesis by suppressing intracellular levels of tumor suppressor lipid sphingosine and enhancing pro-tumorigenic lipid mediator SIP. We propose to further define molecular mechanisms and test the biological significance in mouse models of intestinal cancer. Thus, the specific aims are: 1. To further define the role of sphingosine kinase enzymes in intestinal tumorigenesis. 2. To define the molecular mechanisms involved in the intracellular signaling of sphingosine, 3. We will test the hypothesis that increased intracellular sphingosine and reduced autocrine signaling of 81P brought about by gene deletion of Sphk enzymes is responsible for tumor suppressive action. Dietary sphingomyelin will be used to further Increase sphingosine levels in Sphk knockout mice and we will test whether this dietary manipulation further influences intestinal tumorigenesis in the ApcMin/-t- model. Since sphingolipid levels in the intestine can be altered by dietary means, this research promises to provide a novel means of cancer chemoprevention.